DE60008222T2 - LTA4 HYDROLASE INHIBITORS - Google Patents

Abstract

The invention relates to compounds which constitute a class of medicaments which have an anti-inflammatory activity and which act by inhibiting leukotriene A<SUB>4 </SUB>(LTA<SUB>4</SUB>), and enzyme which is responsible for the biosynthesis of leukotriene LTB<SUB>4</SUB>, a major proinflammatory mediator. The invention also relates to therapeutic anti-inflammatory, applications of these compounds as well as for methods of preparing these compounds.

Description

The present invention relates to the compounds defined below which form a class of medicaments which predominantly have an anti-inflammatory effect and / or by inhibiting LTA ₄ hydrolase (leucotriene A ₄ ), an enzyme which is used for the biosynthesis of leucotriene LTB ₄ , an important pro-inflammatory mediator, is responsible.

she furthermore relates to those compounds which are in the form of active substance precursors (prodrugs) are useful.

she finally affects Process for the preparation of these compounds.

The LTA ₄ hydrolase (EC 3.3.2.6.) Is an enzyme which occurs particularly in the neutrophils and has been shown (Funck et coll. PNAS, 89 (1987), 6677) that its sequence can be compared to that of a zinc -metallopeptidase related to aminopeptidase M (Malfroy et al., BBRC, 161 (1989), 236). In line with the Mafroy et al. it has been recognized that the LTA ₄ hydrolase has a zinc atom which is necessary for its catalytic activity, an aminopeptidase-type activity and a sensitivity to the action of certain inhibitors of the metallopeptidases (Heggstrom et coll., BBRC, 173 (1990) , 431; Minami et coll., BBRC, 173 (1990), 620).

The inhibition of LTA ₄ hydrolase is to prevent the formation of LTB ₄ , a mediator which is responsible for the adhesion of the neutrophils to endothelial cells and their chimiotactism. It appears to be involved in the etiology or symptomatology of a variety of inflammatory conditions and diseases, such as rheumatoid arthritis, chronic intestinal inflammation, platelet sclerosis, gout and psoriasis. In these processes, LTB ₄ could interact synergistically with other arachidonic acid metabolites produced by 5-lipoxygenase or cyclo-oxygenases, the inhibition of which is known to cause anti-inflammatory effects.

Certain compounds with an inhibitory effect on LTA ₄ hydrolase have already been described, in particular in patent applications WO 94/00420, WO 96/11192, WO 96/10999, WO 96/27585, WO 96/41625, WO 98/40354, WO 98/40364, WO 98/40370, WO 98/09943 and WO 98/43954.

The present invention relates to the creation of new compounds that are suitable for inhibiting the LTA ₄ hydrolase.

On Another object of the invention is to compounds create which can be used as medicines.

To this end, the invention relates to the use of compounds of the formula (I) defined below as inhibitors of the activity of LTA ₄ hydrolase, in particular as anti-inflammatory agents.

The The invention further extends to the use of these compounds of the formula (I) in the form of active substance precursors (prodrugs).

in der

• – X ausgewählt ist aus den folgenden Gruppen:
• i) -NH₂
  
• – n₁ und n₃ 0 oder 1 bedeuten, mit der Maligabe, daß (n₁ + n₃) 0 oder 1 ist,
• – n₂ einen Wert von 0 bis 10 aufweist,
• – Y ausgewählt ist aus den folgenden Gruppen:
• i) -O-
• ii) -CH₂-
• iii) -S-
• iv) -NH-
• v) -OCH₂-
• R¹ ausgewählt ist aus den folgenden Gruppen:
• i) dem Wasserstoffatom
• ii) Alkylgruppen
• iii) Cycloalkylgruppen
• iv) Phenylgruppen, die nichtsubstituiert sind oder einfach oder mehrfach substituiert sind mit Substituenten ausgewählt aus Halogenatomen, CF₃-Gruppen, Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten, und Alkoxygruppen, die 1 bis 10 Kohlenstoffatome enthalten, Gruppen der Formeln NH₂, NO₂, CN, OH, CO₂H, OPh, OCH₂Ph, SCH₃, SCH₂CH₃ und NHCOR⁶,
• v) α- oder β-Naphthylgruppen,
• vi) Anthracengruppen,
• vii) Gruppen der Formel -A²-(CH₂)_n4-A¹, in der n₄ einen Wert von 0 bis 4 aufweist, A¹ und A² unabhängig voneinander ausgewählt sind aus den folgenden Gruppen:
• a) Cycloalkylgruppen
• b) Phenylgruppen, die nicht substituiert sind oder einfach oder mehrfach substituiert sind durch Substituenten ausgewählt aus Halogenatomen, CF₃-Gruppen und Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten, und Alkoxygruppen, die 1 bis 10 Kohlenstoffatome enthalten,
• c) 2-, 3- oder 4-Pyridyl
• d) 2- oder 3-Thienyl
• e) 2- oder 3-Furyl
• f) 2-, 3- oder 4-Piperidyl
• g) Cycloalken
• viii) 2-, 3- oder 4-Pyridylgruppen
• ix) 2- oder 3-Thienylgruppen
• x) 2- oder 3-Furylgruppen
  
• – Z ausgewählt ist aus den folgenden Gruppen:
• i) -COOR⁷
  
• v) -SO₃H;
• vi) -SO₂NHR¹¹
• vii) -CONHSO₂R¹¹
• – R² und R³ unabhängig voneinander ausgewählt sind aus den foglenden Gruppen:
• i) Wasserstoffatomen
• ii) Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten
• iii) Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten und durch ein Halogenatom substituiert sind
• iv) CF₃-Gruppen
• v) Halogenatomen
• – R⁴ und R⁵ unabhängig voneinander ausgewählt sind aus Wasserstoffatomen, Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten, Phenylgruppen, die nicht substituiert sind oder durch ein Halogenatom, eine CF₃-Gruppe, eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome enthält, eine Alkoxygruppe, die 1 bis 10 Kohlenstoffatome enthält, oder eine OH-Gruppe substituiert sind,
• – n₅ einen Wert von 0 bis 2 aufweist,
• – R⁶ eine Alkylgruppe bedeutet, die 1 bis 10 Kohlenstoffatome enthält
• – R⁷ ein Wasserstoffatom, eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome enthält, eine Gruppe -(CH₂)_n6-Ph bedeutet, worin n₆ einen Wert von 0 bis 4 aufweist und Ph eine Phenylgruppe bedeutet, die nicht substituiert ist oder einfach oder mehrfach substituiert ist durch ein Halogenatom, eine Gruppe CF₃, eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome enthält, eine Alkoxygruppe, die 1 bis 10 Kohlenstoffatome enthält, oder eine OH-Gruppe,
• – R⁸ und R⁹ unabhängig voneinander ausgewählt sind aus Wasserstoffatomen, Phenylgruppen, Alkylgruppen, die 1 bis 10 Kohlenstoffatome enthalten, und Acetylthioalkylengruppen, die 1 bis 10 Kohlenstoffatome enthalten,
• – R¹⁰ eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome enthält, eine Gruppe -(CH₂)_n7-Ph bedeutet, worin n₇ einen Wert von 1 bis 6 aufweist und Ph eine Phenylgruppe darstellt, die nicht substituiert ist oder einfach oder mehrfach substituiert ist durch ein Halogenatom, eine CF₃-Gruppe, eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome aufweist, oder eine Alkoxygruppe, die 1 bis 10 Kohlenstoffatome aufweist,
• – R¹¹ eine Alkylgruppe, die 1 bis 10 Kohlenstoffatome enthält, oder eine Phenylgruppe bedeutet.

These compounds correspond to the following formula (I):

in the

• - X is selected from the following groups:
• i) -NH ₂
  
• N ₁ and n _{3 are} 0 or 1, with the malignant that (n ₁ + n ₃ ) is 0 or 1,
• N _{2 has} a value from 0 to 10,
• - Y is selected from the following groups:
• i) -O-
• ii) -CH ₂ -
• iii) -S-
• iv) -NH-
• v) -OCH ₂ -
• R ^{1 is} selected from the following groups:
• i) the hydrogen atom
• ii) alkyl groups
• iii) cycloalkyl groups
• iv) phenyl groups which are unsubstituted or mono- or polysubstituted with substituents selected from halogen atoms, CF ₃ groups, alkyl groups which contain 1 to 10 carbon atoms, and alkoxy groups which contain 1 to 10 carbon atoms, groups of the formulas NH ₂ , NO ₂ , CN, OH, CO ₂ H, OPh, OCH ₂ Ph, SCH ₃ , SCH ₂ CH ₃ and NHCOR ⁶ ,
• v) α- or β-naphthyl groups,
• vi) anthracene groups,
• vii) Groups of the formula -A ² - (CH ₂ ) _n4 -A ¹ , in which n _{4 has} a value from 0 to 4, A ¹ and A ² are selected independently of one another from the following groups:
• a) Cycloalkyl groups
• b) phenyl groups which are unsubstituted or mono- or polysubstituted by substituents selected from halogen atoms, CF ₃ groups and alkyl groups which contain 1 to 10 carbon atoms and alkoxy groups which contain 1 to 10 carbon atoms,
• c) 2-, 3- or 4-pyridyl
• d) 2- or 3-thienyl
• e) 2- or 3-furyl
• f) 2-, 3- or 4-piperidyl
• g) cycloalkene
• viii) 2-, 3- or 4-pyridyl groups
• ix) 2- or 3-thienyl groups
• x) 2- or 3-furyl groups
  
• - Z is selected from the following groups:
• i) -COOR ⁷
  
• v) -SO ₃ H;
• vi) -SO ₂ NHR ¹¹
• vii) -CONHSO ₂ R ¹¹
• - R ² and R ^{3 are} independently selected from the following groups:
• i) hydrogen atoms
• ii) alkyl groups containing 1 to 10 carbon atoms
• iii) alkyl groups containing 1 to 10 carbon atoms and substituted by a halogen atom
• iv) CF ₃ groups
• v) halogen atoms
• - R ⁴ and R ^{5 are} independently selected from hydrogen atoms, alkyl groups which contain 1 to 10 carbon atoms, phenyl groups which are unsubstituted or by a halogen atom, a CF ₃ group, an alkyl group which contains 1 to 10 carbon atoms, a Alkoxy group, the 1 to 10 Koh contains lenstoffatome, or an OH group are substituted,
• N _{5 has} a value from 0 to 2,
• R ^{6 represents} an alkyl group containing 1 to 10 carbon atoms
• R ^{7 represents} a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, a group - (CH ₂ ) _n6 -Ph, in which n _{6 has} a value of 0 to 4 and Ph represents a phenyl group which is unsubstituted or simple or is substituted several times by a halogen atom, a group CF ₃ , an alkyl group which contains 1 to 10 carbon atoms, an alkoxy group which contains 1 to 10 carbon atoms, or an OH group,
• R ⁸ and R ⁹ are selected independently of one another from hydrogen atoms, phenyl groups, alkyl groups which contain 1 to 10 carbon atoms and acetylthioalkylene groups which contain 1 to 10 carbon atoms,
• R ^{10 is} an alkyl group containing 1 to 10 carbon atoms, a group - (CH ₂ ) _n7 -Ph, in which n _{7 has} a value of 1 to 6 and Ph represents a phenyl group which is unsubstituted or mono- or polysubstituted is represented by a halogen atom, a CF ₃ group, an alkyl group which has 1 to 10 carbon atoms, or an alkoxy group which has 1 to 10 carbon atoms,
• R ^{11 represents} an alkyl group containing 1 to 10 carbon atoms or a phenyl group.

Under A lower alkyl group means an alkyl group with a straight one or branched chain, preferably 1 to 10 carbon atoms Contains 1 to 4 carbon atoms.

Under A lower alkoxy group means an alkoxy group which is a straight-chain or branched chain with 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.

Under a cycloalkyl group means a ring which has 5 to 7 carbon atoms, preferably 6 carbon atoms, such as cyclopentane, cyclohexane or cycloheptane.

Under A cycloalkene group means a ring that has 5 to 7 carbon atoms contains and has a double bond, preferably 6 carbon atoms, like cyclohexene.

Under A lower acetylthioalkylene group means an acetylthio group with a straight chain, the 1 to 4 carbon atoms, preferably 1 contains up to 2 carbon atoms.

The Halogen atoms are preferably selected from chlorine and fluorine.

The The invention further extends to the isomers of the compounds of formula (I), including the diastereoisomeric and enantiomeric forms.

The Invention also extends to the therapeutically acceptable Salts of these compounds as well as the salts of their isomers including the diastereoisomeric and enantiomeric forms.

Under therapeutically acceptable salts are understood to mean a salt that neither the chemical structure and the pharmacological properties of the compounds of the invention changed. Such salts close inorganic and organic anions such as the hydrochloride, the Hydrobromide, acetate, trifluoroacetate, maleate, fumarate, the oxalate, etc., which are well known in the art are. These salts are prepared in the usual way by neutralization of the compounds of formula (I) with the desired acid.

• (α) den Verbindungen, bei denen Z eine Gruppe des Typs COOR⁷, n₁ = n₃ = 0 und R² = H bedeuten und R¹ eine nichtsubstituierte oder einfach- oder polysubstituierte Phenylgruppe vom Typ iv) bedeutet und bei denen n₂ = 1 bedeutet, und
• (β) die folgenden Verbindungen: α-Amino-β-phenoxy-propionsäure, 3-Amino-7-phenyl-heptansäure, 3-Amino-6-phenoxy-hexansäure, α-Amino-6-phenyl-hexansäure und α-Amino-5-phenoxy-pentansäure.

The invention further extends to the compounds of formula (I) as defined, with the exception of:

• (α) the compounds in which Z is a group of the type COOR ⁷ , n ₁ = n ₃ = 0 and R ² = H and R ^{1 is} an unsubstituted or mono- or polysubstituted phenyl group of type iv) and in which n ₂ = 1 means and
• (β) the following compounds: α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α-amino-6-phenyl-hexanoic acid and α-amino -5-phenoxy-pentanoic acid.

The The invention further relates to pharmaceutical preparations which at least contain such a connection.

The inventors have shown that the compounds of formula (I) defined above or their salts, which are obtained with inorganic or organic, therapeutically compatible salts, or their stereoisomers have a strong inhibitory effect on LTA ₄ hydrolase.

The Compounds (I) continue to have good biological availability and have proven to be less toxic.

The present invention describes a series of compounds that are capable of strongly inhibiting LTA ₄ hydrolase.

This Connections also have a biological effect as stated below, the gives them a therapeutic interest.

According to a first embodiment of the invention, a preferred group of compounds of the formula (I) above includes those in which X NH ₂ and / or Z denotes the group -COOR ⁷ , in which R ^{7 represents} a hydrogen atom.

Of this group, the compounds of the formula (I) in which X is NH ₂ and Z are COOH are particularly preferred.

The compounds of formula (I) in which R ² and / or R ^{3 represent} a hydrogen atom also form a particularly preferred subgroup of the invention.

R ² and R ³ each preferably represent a hydrogen atom.

The compounds of formula (I) in which R ² and / or R ³ are different from hydrogen form a further subgroup according to the invention.

A subfamily of the above-mentioned compounds is formed by the compounds in which n ₁ and n _{3 are} equal to 0.

Another subfamily is formed by the compounds in which n ₁ or n _{3 is} different from 0.

A subclass of the compounds according to the invention is further formed by those in which n ₂ = 0. In these compounds, Y is preferably -O-.

A further subclass is formed by the compounds in which n ₂ varies from 1 to 5, preferably from 2 to 5, and those compounds in which n ₂ = 3 are particularly preferred.

Another class of compounds according to the invention is defined in that n _{2 is} greater than 5.

Regarding the Symbols Y are the compounds where Y is a hydrogen atom means, especially according to the invention prefers.

Further subfamilies can be defined depending on the fact that Y represents -CH ₂ -, a sulfur atom, a group -NH- or a group -OCH ₂ -.

R ¹ is preferably selected from an unsubstituted or substituted phenyl group, which is more preferably monosubstituted by one of the above-mentioned substituents.

When R ^{1 represents} a substituted phenyl group, the substituent (s) are preferably selected from lower alkyl groups, lower alkoxy groups, OPh and OCH ₂ Ph.

The compounds in which R ^{1 represents} a phenyl group mono- or polysubstituted by the OPh group form a subfamily preferred according to the invention.

If R ^{1 represents} a group -A ² - (CH ₂ ) _n4 -A ¹ , A ² preferably denotes a phenyl group, preferably an unsubstituted phenyl group.

In these compounds, n _{4 is} preferably 0 or 1 and A ¹ is preferably made of Phe nyl, cycloalkyl and cycloalkene group selected.

The group R ¹ , which is a group A ² - (CH ₂ ) _n4 -A ¹ , is preferably a phenyl group, which is replaced by a group Ph, CH ₂ Ph, CH ₂ -cycloalkyl or CH ₂ -cycloalkene, more preferably CH ₂ Ph or CH ₂ cycloalkyl is substituted.

Another subfamily includes the compounds (I) in which R ^{1 represents} a hydrogen atom or a lower alkyl group.

A further subfamily comprises the compounds (I), in which R ^{1 represents} a cycloalkyl group.

The compounds (I) in which R ¹ denotes an α- or β-naphthyl group or an anthracene group also form a further subfamily.

Another group of compounds according to the invention comprises the compounds (I), in which R ¹ denotes a 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2- or 3-furyl group.

darstellt, bilden ebenfalls eine weitere erfindungsgemäße Untergruppe.The compounds (I), wherein R ^{1 is} a group

represents also form a further subgroup according to the invention.

at all mentioned above Subfamilies can the undefined substituents depending on those given above general definitions vary.

in der X, n₂, n₃, Y, R¹ und R⁷ die oben angegebenen Bedeutungen besitzen.A particularly preferred group of compounds according to the invention is formed by the compounds which correspond to the following formula (II):

in which X, n ₂ , n ₃ , Y, R ¹ and R ^{7 have} the meanings given above.

The above for the compounds of formula (I) specified preferences meet also to the compounds of formula (II).

in der n₂, n₃, Y und R¹ die oben angegebenen Bedeutungen besitzen.Another particularly preferred group comprises the compounds of the following formula (III):

in which n ₂ , n ₃ , Y and R ^{1 have} the meanings given above.

The special selections given for the compounds of the formula (I) with regard to the symbols Y and R ¹ also apply to the compounds of the formulas (III).

in der Y, n₂ und n₃ die oben angegebenen Bedeutungen besitzen und Ar für die Gruppe R¹ steht, die eine Phenylgruppe iv) darstellt, die gegebenenfalls substituiert ist, wie es oben definiert worden ist, oder worin R¹ eine Gruppe vii) -A²-(CH₂)_n4-A¹, worin A² eine gegebenenfalls substituierte Phenylgruppe (b), wie sie oben definiert worden ist, darstellt, bedeutet, besonders bevorzugt.Of these compounds, those are those which correspond to the following formula (IV):

in which Y, n ₂ and n _{3 have} the meanings given above and Ar represents the group R ¹ which represents a phenyl group iv) which is optionally substituted, as defined above, or in which R ^{1 represents} a group vii) -A ² - (CH ₂ ) _n4 -A ¹ , in which A ^{2 represents} an optionally substituted phenyl group (b), as defined above, is particularly preferred.

bedeutet, worin R⁸ und R⁹ ein Wasserstoffatom bedeuten und R¹⁰ die oben angegebenen Bedeutungen besitzt.According to a second embodiment of the invention, a preferred group of compounds of the aforementioned formula (I) includes those in which X is NH ₂ and / or Z is the group

means in which R ⁸ and R ^{9 represent} a hydrogen atom and R ^{10 has} the meanings given above.

bedeuten, besonders bevorzugt.From this group are the compounds of formula (I) in which X NH ₂ and Z

mean, particularly preferred.

The compounds of formula (I) in which R ² and / or R ^{3 represent} a hydrogen atom also form a particularly preferred subgroup according to the invention.

R ² and R ³ each preferably represent a hydrogen atom.

The compounds of formula (I) in which R ² and / or R ³ are different from hydrogen form a further subgroup of the invention.

A Subfamily of the above connections is through the connections formed, in which n1 and n3 each represent 0.

A further subfamily is formed by the connections in which n1 and / or n3 are different from 0.

A subclass of the compounds according to the invention is formed by those in which n ₂ = 0. In these compounds, Y is preferably -O-.

A further subclass is formed by the compounds in which n ₂ varies from 1 to 5, preferably from 2 to 5, with particular preference being given to the compounds in which n ₂ = 3.

Another class of compounds according to the invention is defined by those in which n _{2 is} greater than 5.

in the With regard to the symbol Y are the connections where this Radical represents an oxygen atom, particularly preferred according to the invention.

Further subfamilies can be defined depending on the fact that Y represents -CH ₂ -, a sulfur atom or a group -NH- or -OCH ₂ -.

R ¹ is preferably selected from unsubstituted or substituted phenyl groups, preferably phenyl groups which are monosubstituted by the abovementioned substituents.

When R ^{1 represents} a substituted phenyl group, the substituent (s) are preferably selected from halogen atoms, CF ₃ groups, lower alkyl groups, lower alkoxy groups, NO ₂ , CN, NH ₂ , CO ₂ H, OPh, OCH ₂ Ph and NHCOR ⁸ .

The compounds in which R ^{1 represents} a phenyl group mono- or polysubstituted by halogen atoms or lower alkyl groups form a further subfamily of the invention.

If R ^{1 represents} a radical -A ² - (CH ₂ ) _n4 -A ¹ , A ² preferably denotes a phenyl group, preferably an unsubstituted phenyl group.

In these compounds, n _{4 is} preferably 0 or 1 and / or A ¹ is preferably a phenyl group.

If R ¹ _denotes a radical -A ² - (CH ₂ ) _n4 -A ¹ , it is a phenyl group which is substituted by a group Ph or CH ₂ Ph, more preferably CH ₂ Ph.

Another subfamily includes the compounds (I) in which R ^{1 represents} a hydrogen atom or a lower alkyl group.

Another subfamily comprises the compounds (I) in which R ^{1 represents} a cycloalkyl group.

The compounds (I) in which R ^{1 represents} an α- or 1-naphthyl group or an anthracene group form a further subfamily.

Another group of compounds according to the invention comprises the compounds (I) in which R ^{1 represents} a 2-, 3- or 4-pyridyl, 2- or 3-thienyl or 2- or 3-furyl group.

darstellt, bilden ebenfalls eine weitere erfindungsgemäße Untergruppe.The compounds (I), wherein R ^{1 is} a group of the formula

represents also form a further subgroup according to the invention.

at all mentioned above Subfamilies can the not specified Substituents dependent vary from their respective general definitions.

in der X, n₂, Y, R¹, R⁸ und R⁹ die oben angegebenen Bedeutungen besitzen.A particularly preferred group of the compounds according to the invention is formed by the compounds of the following formula (V):

in which X, n ₂ , Y, R ¹ , R ⁸ and R ^{9 have} the meanings given above.

The for the Compounds of formula (I) above preferences also refer to the compounds of formula (V).

in der n₂, Y und R¹ die oben angegebenen Bedeutungen besitzen.Another particularly preferred group includes the compounds

in which n ₂ , Y and R ^{1 have} the meanings given above.

The special selections mentioned for the compounds of formula (I) with regard to the sym bole Y and R ¹ also apply to the compounds of the formulas (VI).

in der Y und n₂ die oben angegebenen Bedeutungen besitzen, Ar für R¹ steht, welches eine gegebenenfalls substituierte Phenylgruppe iv), wie sie oben definiert worden ist, oder R¹ eine Gruppe vii) -A²-(CH₂)_n4-A¹ darstellt, worin A² eine gegebenenfalls substituierte Phenylgruppe (b), wie sie oben definiert worden ist, bedeutet, besonders bevorzugt.Of these compounds, those of the following formula (VII) are:

in which Y and n _{2 have} the meanings given above, Ar represents R ¹ , which is an optionally substituted phenyl group iv), as defined above, or R ^{1 represents} a group vii) -A ² - (CH ₂ ) _n4 - A ¹ represents, in which A ^{2 represents} an optionally substituted phenyl group (b), as defined above, is particularly preferred.

in der X, Y, n₂, R¹, R⁸ und R¹⁰ die oben angegebenen Bedeutungen besitzen.Another group of compounds according to the second embodiment of the invention comprises the compounds of the following formula

in which X, Y, n ₂ , R ¹ , R ⁸ and R ^{10 have} the meanings given above.

The for the Compounds of formula (I) meet the preferences given above also to these compounds of formula (VIII).

darstellt.A third embodiment of the invention relates in particular to the compounds of the formula (I) in which Z represents the group

represents.

A fourth embodiment of the invention relates in particular to the compounds of the formula (I) in which Z denotes a group -SO ₃ H, -SO ₂ NHR ¹¹ or -CONHSO ₂ R ¹¹ .

Of The compounds of the present invention are special as follows prefers:

1) - (S) -O-4-Benzylphenoxyserin hydrochloride

2) 2- (RS) -amino-6- (4-benzylphenoxy) hexanoic acid hydrobromide

3) 2- (RS) -amino-5- (4-benzylphenoxy) pentanoic acid hydrobromide

4) 2- (RS) -amino-5- (4-phenoxyphenoxy) pentanoic acid hydrobromide

5) 2- (RS) -amino-7- (4-benzyl-phenoxy) -heptanoic acid hydrobromide

6) 2- (RS) -amino-6- (4-phenylphenoxy) hexanoic acid hydrobromide

7) 2- (RS) -amino-6- (4-hexyloxyphenoxy) hexanoic acid hydrobromide

8) 2- (RS) -amino-8- (4-benzylphenoxy) octanoic acid hydrobromide

9) 2- (RS) -amino-6- (4-phenoxyphenoxy) hexanoic acid hydrobromide

10) 2- (RS) -aminomethyl) -6- (4-benzylphenoxy) hexanoic acid

11) 1- (RS) -amino-5- (phenoxy) -pentylphosphonic acid hydrobromide

12) 1- (RS) -amino-6- (phenoxy) hexylphosphonic acid hydrobromide

13) 1- (RS) -amino-5- (4-benzylphenoxy) pentylphosphonic acid hydrobromide

14) 1- (RS) -amino-4- (phenoxy) butylphosphonic acid hydrobromide

15) 1- (RS) -amino-7- (phenoxy) -heptylphosphonic acid hydrobromide

16) 2- (RS) -amino-6- (4-cyclohexylmethylphenoxy) hexanoic acid hydrobromide

17) 3- (RS) -amino-7- (4-benzylphenoxy) heptanoic acid

18) 2- (RS) -Amino-2-methyl-6- (4-benzylphenoxy) hexanoic acid hydrobromide

19) 1- (RS) -amino-tridecanyl-phosphonic acid hydrobromide

20) 3- (RS) -amino-5- (4-benzylphenoxy) pentanoic acid

21) 3- (RS) -amino-6- (4-benzylphenoxy) hexanoic acid

The compounds of the formula (I) or (II), as defined above, in which X is NH ₂ and R ⁷ is different from a hydrogen, form active substance precursors (prodrugs).

und R⁷ ein Wasserstoffatom bedeuten, bilden ebenfalls Wirkstoffvorläufer.The compounds of formula (I) or (II) as defined above wherein

and R ^{7 represents} a hydrogen atom, also form active substance precursors.

und R⁷ von einem Wasserstoff verschieden ist, bilden Wirkstoffvorläufer.The compounds of formula (I) or (II) as defined above

and R ⁷ is different from a hydrogen form drug precursors.

The compounds of formula (I) or (V) as defined above, wherein X NH ₂ and R ⁸ and R ⁹ are different from a hydrogen atom, form active ingredient precursors.

The compounds of formula (I) or (V) as defined above, wherein X is NH ₂ , R ^{8 is} hydrogen and R ⁹ is different from a hydrogen atom, form active ingredient precursors.

bedeutet und R⁸ und R⁹ von einem Wasserstoffatom verschieden sind, bilden Wirkstoffvorläufer.The compounds of formula (I) or (V) as defined above

means and R ⁸ and R ⁹ are different from a hydrogen atom, form active substance precursors.

bedeutet und R⁸ und R⁹ Wasserstoff bedeuten, bilden Wirkstoffvorläufer.The compounds of formula (I) or (V) as defined above

means and R ⁸ and R ^{9 are} hydrogen, form active substance precursors.

bedeutet und R⁸ Wasserstoff bedeutet und R⁹ von einem Wasserstoffatom verschieden ist, bilden Wirkstoffvorläufer.The compounds of formula (I) or (V) as defined above wherein

means and R ⁸ means hydrogen and R ⁹ is different from a hydrogen atom, form active substance precursors.

The compounds of formula (I) or (VIII) as defined above, wherein X is NH ₂ and R ⁸ is different from a hydrogen atom, form active ingredient precursors.

bedeutet und R⁸ von einem Wasserstoffatom verschieden ist, bilden Wirkstoffvorläufer.The compounds of formula (I) or (VIII) as defined above, wherein X

means and R ⁸ is different from a hydrogen atom, form active substance precursors.

bedeutet und R⁸ Wasserstoff darstellt, bilden Wirkstoffvorläufer.The compounds of formula (I) or (VIII) as defined above, wherein X

means and R ^{8 represents} hydrogen, form active substance precursors.

Examples for active substance precursors according to the invention (prodrugs) are the following:

22) 2- (RS) -amino-7- (4-benzyl-phenoxy) -heptanoic acid ethyl ester hydrochloride

23) Ethyl 2- (RS) -amino-6- (4-benzylphenoxy) hexanoate hydrochloride

24) Diphenyl-1-amino-5-phenoxypentylphosphonate hydrobromide

25) Ethyl hydrogen 1-amino-5-phenoxypentylphosphonate hydrobromide

The Compounds of the present invention can be obtained from readily available starting materials according to the following specified procedures are produced.

The reaction schemes given below describe processes the for the preparation of the compounds of formula (I) can be used can, with the starting products, the intermediates as well as the synthesis conditions specify.

The abbreviations used in the present description correspond to the following definitions: Ac: acetyl bn: benzyl DIAD: diisopropylazodicarboxylate DMF: dimethylformamide DPPA: diphenylphosphorylazide et: ethyl EtOH: ethyl alcohol Et ₂ O: ethyl ether me: methyl NBu ₄ F: tetrabutylammonium Pd / C: Palladium on carbon Ph: phenyl THF: tetrahydrofuran PCC: Pyridinium chlorochromate

The Schemes 1 to 5 describe the production of substituted ones Amino acids.

Scheme 1

• a) SOCl ₂ , EtOH, reflux
• b) NEt ₃ , Et ₂ O, CHCl ₃
• c) Me ₃ SiCl, NEt ₃
• d) MeOH
• e) Et ₃ N / (Ph) ₃ CCl
• f) NBu ₄ F 1 M / THF
• g) PPh ₃ , DEAD or DIAD, R ¹ OH
• h) HCO ₂ H; NaHCO ₃
• i) NaOH N; 2 N HCl

Serine is esterified in the presence of thionyl chloride and EtOH. The hydrochloride of the amino ester 1 obtained is treated with triethylamine and then with trimethylsilyl chloride in the presence of NEt ₃ to form compound 2. The amino function is freed from the protective group with the aid of anhydrous MeOH and then protected again by reaction with trityl chloride. The hydroxy function is then released using tetrabutylammonium fluoride to form compound 3. The hydroxy function of compound 3 is substituted with a phenol derivative of formula R ¹ OH using a Mitsunobu type reaction to form compound 4. Compounds 5 are obtained by Deprotection with formic acid followed by treatment with sodium hydrogen carbonate. The amino acid hydrochloride 6 is obtained by saponifying the compound 5 in NaOH, followed by acidification in 2 N HCl.

you prepares the amino acid derivatives 13 and 15 starting from the malonic esters 10 obtained starting from commercial Halides or starting from the halides 9.

W = Cl, Br
Y = O, S
n₂ und R¹ besitzen die bezüglich der Formel (I) angegebenen Bedeutungen

• a) 9 N NaOH, THF am Rückfluß
• b) K₂CO₃, DMF, Raumtemperatur

Scheme 2 describes the preparation of non-commercially available halides 9. Scheme 2

W = Cl, Br
Y = O, S
n ₂ and R ¹ have the meanings given for the formula (I)

• a) 9 N NaOH, THF at reflux
• b) K ₂ CO ₃ , DMF, room temperature

The compounds 9 can be obtained in two ways: by treatment in 9 N sodium hydroxide solution under reflux in the presence of THF or by using powdered K ₂ CO ₃ in DMF at room temperature.

R₃, n₂, Y und R¹ besitzen die bezüglich der Formel (I) angegebenen Bedeutungen.

• a) KOH, EtOH, 0°C
• b) DPPA, NEt₃, Toluol, Benzylalkohol, 80°C
• c) H₂, Pd/C, EtOH
• d) 3 N HCl
• e) NaOH, MeOH; 1 N HCl
• f) HBr/CH₃CO₂H

Scheme 3 describes the synthesis of amino esters 13 and amino acids 15. Scheme 3

R ₃ , n ₂ , Y and R ¹ have the meanings given for the formula (I).

• a) KOH, EtOH, 0 ° C
• b) DPPA, NEt ₃ , toluene, benzyl alcohol, 80 ° C
• c) H ₂ , Pd / C, EtOH
• d) 3N HCl
• e) NaOH, MeOH; 1N HCl
• f) HBr / CH ₃ CO ₂ H

The malonic acid esters of formula 10 are obtained by alkylating a malonic acid ester with the corresponding bromine or chlorine derivatives 9 in the presence of sodium ethylate in ethanol at reflux. Mono-saponification with the aid of a KOH solution in EtOH leads to the compounds 11, which are subjected to a Curtius reaction in the presence of DPPA, NEt ₃ and benzyl alcohol in toluene at 80 ° C. overnight.

The Benzyloxycarbonylfunction is in by catalytic hydrogenation Cleave ethanol using Pd / C to form the amino esters 13. Saponification of the compounds 12 with the aid of a NaOH solution in MeOH leads to the derivatives 14, which are subjected to the action of HBr in acetic acid to form the amino acids 15th

The amino acid derivatives 18 and 19 are obtained starting from the malonic esters 10 (in which R ³ = H), as described in Scheme 3.

The Scheme 4 describes the synthesis of the salts of amino esters 19 and of amino acids 18th

Scheme 4

• a) 6 N NaOH, reflux
• b) paraformaldehyde, HNEt ₂ , ACOEt
• c) NH ₂ OH HCl, NaOEt / EtOH
• d) SOCl ₂ , ROH

you prepares the acrylic acids 17 over the dicarboxylic acids 16, which is saponified in 6 N sodium hydroxide solution Reflux and then by a Mannich reaction in the presence of paraformaldehyde, diethylamine obtained in reflux in ethyl acetate.

you receives the derivatives 18 by adding hydroxylamine to the acrylic acids 17 at reflux in the presence of sodium ethylate. The salts of amino esters 19 are formed starting from of the derivatives 18 by reaction in the presence of thionyl chloride in an alcohol ROH.

The Scheme 5 illustrates the preparation of the β-amino acids 24 and the salts of the amino acids 25 starting from of malonic acid esters.

Scheme 5

• a) 6 N NaOH, reflux
• b) Decarboxylation by heating
• c) LiAlH ₄ , Et ₂ O
• d) PCC, CH ₂ Cl ₂
  
  , NaH, THF
• f) 1N NaOH, MeOH
• g) NH ₂ OH HCl, NaOEt / EtOH, reflux
• h) SOCl ₂ , ROH

you receives the malonic esters of formula 20 by alkylating a malonic acid ester with the corresponding Bromine or chlorine derivatives in the presence of sodium ethylate in ethanol at reflux. You prepare the acids 21 over the dicarboxylic acids obtained by saponification in 6 N sodium hydroxide solution at reflux and by a thermal Decarboxylation. After a reduction with the help of lithium aluminum hydride followed oxidation with pyridinium chlorochromate (PCC) gives that Aldehyde 22. Amino acids 24 are prepared via a Wittig-Horner reaction using triethylphosphonoacetate, followed by saponification in the presence of 1 N sodium hydroxide solution and then by addition of hydroxylamine in the presence of sodium ethylate to the acrylic acid derivatives.

you prepares the salts of amino esters 25 starting from the derivatives 24 by reaction in the presence of thionyl chloride in an alcohol RAW.

The Schemes 6 and 7 describe the preparation of the aminophosphonic acid derivatives 28th

you receives the amino-phosphonic acid derivatives 28 in two ways:

Path A (Scheme 6) Scheme 6

• a) CH ₃ COCl, -5 ° C, 10 minutes 0 ° C, 1 hour room temperature, 5 hours
• b) HBr 30% / CH ₃ CO ₂ H, 24 hours

you converts the phosphite 26 with benzyl carbamate and the aldehydes 22 for the formation of the phosphonates 27. By deprotection with Using 30% HBr in acetic acid receives derivatives 28.

Route B (Scheme 7): Scheme 7

• a) NaH, DMF
• b) 1N LiOH, MeOH
• c) DPPA, NEt ₃ , toluene, benzyl alcohol, 80 ° C
• d) HBr 30% / CH ₃ CO ₂ H, 24 hours

you alkylates the phosphonoacetates 29 with the halogen derivatives 9 Help from NaH in DMF. After saponification and the Curtius reaction receives the phosphonates 27. By splitting off the protective group with the help of 30% HBr in acetic acid receives derivatives 28.

The Scheme 8 illustrates the preparation of the aminophosphonic acid derivatives 31 and 33.

Scheme 8

• a) HBr, CH ₃ COOH, 1 hour
• b) 2N NaOH, NBu ₄ Br
• c) HBr 30% / CH ₃ COOH, 1 hour

you subject compound 27 to the action of a 30% HBr solution in acetic acid to form the product 31.

you receives the compound 33 in two stages starting from the derivatives 27: by simple saponification in the presence of a phase transfer agent in 2 N NaOH and by splitting off the protective group with 30% HBr in acetic acid.

The inventors have shown that the compounds (I) according to the invention, in particular the compounds which in particular correspond to one of the formulas (II) to (VIII), have inhibitory effects on LTA ₄ hydrolase.

These properties also apply to the compounds of the formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted or mono- or polysubstituted phenyl group of the type iv ) means and n _{2 has} the value 1, as well as the α-amino-β-phenoxy-propionic acid, the 3-amino-7-phenyl-heptanoic acid, the 3-amino-6-phenoxy-hexanoic acid, the α-amino-6 -phenyl-hexanoic acid and the α-amino-5-phenoxy-pentanoic acid.

she have interesting therapeutic properties, especially on the field of inflammation treatment.

she also have an interesting anti-arthritic effect.

The mentioned above compounds of the invention continue to have anti-psoriasis effects.

Furthermore, the inventors have shown that these compounds according to the invention prevent the increase in the increase in LTB ₄ levels in the tissue induced by the cyclooxygenase inhibitors.

They continue to be effective in preventing certain paradoxical pro-inflammatory side effects effects of cyclooxygenase inhibitors.

Since LTB _{4 is} the endogenous ligand of the receptor, which causes the peroxysomes to multiply, the compounds according to the invention continue to be used in the field of liver protection and have an antimitotic effect.

The invention therefore also relates to the use of the compounds of the formula (I), in particular of the compounds which in particular correspond to one of the formulas (II) to (VIII) and a compound of the formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted or mono- or polysubstituted phenyl group of the type iv) and n ₂ = 1, and also α-amino-β-phenoxy-propionic acid, 3-amino -7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α-amino-6-phenyl-hexanoic acid and α-amino-5-phenoxy-pentanoic acid as drugs with an effect as inhibitors of the action of LTA ₄ Hydrolase, especially for anti-inflammatory or antiarrhythmic treatment.

she further relates to the use of these compounds as antipsoriasis drugs.

she further concerns their use as liver protection and as antimitotic drugs.

It further relates to the use of these compounds as medicaments for the treatment of an overproduction of LTB ₄ , which is induced in particular by cyclooxygenase inhibitors.

It further relates to the use of these compounds, in particular the compounds which correspond in particular to one of the formulas (II) to (VIII), for the production of medicaments for inhibiting the action of LTA ₄ hydrolase.

she particularly relates to their use in the manufacture of medicinal products for the treatments indicated above.

This Connections, and especially the connections, in particular one of the formulas (II) to (VIII) can correspond in a physiological acceptable carrier material or binders can be administered.

As a result, The present invention also relates to pharmaceutical preparations, which is a therapeutically effective amount of at least one compound of formula (I) in combination with a physiologically acceptable support material or contain binders.

The Compounds (I), and in particular the compounds, in particular one of the formulas (II) to (VIII) of the invention may also can be used in combination with cyclooxygenase inhibitors.

The The invention therefore also relates to pharmaceuticals or pharmaceuticals Preparations containing a therapeutically effective amount of a compound (I) and in particular of compounds which are in particular one of the Formulas (II) to (VIII) correspond, and a therapeutically effective one Amount of a compound that is a cyclooxygenase inhibiting compound represents, optionally in combination with a physiological acceptable carrier material or contain binders.

Examples for suitable according to the invention Cyclooxygenase inhibitors are aspirin (acetylsalicylic acid), ibuprofen and diclofenac.

The Medicaments according to the invention or pharmaceutical preparations can advantageously be local Ways across the skin or eyes, administered parenterally or orally , the latter being preferred.

The invention further extends to a treatment method for inhibiting the action of LTA ₄ hydrolase in humans.

she further relates to such a method for the treatments indicated above.

It further relates to a method for treating an overproduction of LTB ₄ , which is particularly induced by cyclooxygenase inhibitors.

Further Advantages and characteristics of the present invention result from reading the examples of the preparation of the compounds of formula (I) which hereinafter in explanatory and not restrictive Be specified as well as the biological specified below Results.

EXAMPLES

The following table includes a summary of examples of compounds of the formula (I):

example 1

11.98 g (90 mmol) of serine ethyl ester in the form of the hydrochloride are dissolved in 155 ml of CH ₂ Cl ₂ . Then 22.78 g (209.68 mmol) of trimethylsilyl chloride are added under an inert atmosphere.

The mixture is heated to reflux for 20 minutes and then brought to room temperature. Then 21.2 g (209.90 mmol) of triethylamine in 60 ml of CH ₂ Cl ₂ are added and the mixture is heated under reflux for 45 minutes.

The mixture is then cooled to 0 ° C. and a solution of 5.4 ml (135 mmol) of anhydrous methanol in 22 ml of CH ₂ Cl ₂ is added.

The temperature of the medium is allowed to rise to room temperature and then 9.1 g (90 mmol) of NEt ₃ and 25 g (90 mmol) of trityl chloride are added in succession and the mixture is stirred overnight at room temperature.

The mixture is concentrated in vacuo, taken up with 200 ml of Et ₂ O and washed with water (once with 30 ml).

It is dried over MgSO ₄ , filtered and concentrated in vacuo.

you receives 38.8 g of the desired Connection.

Example 2

50 ml of a 1 M solution of tetrabutylammonium fluoride (NBu ₄ F) in THF are added to a solution of 38.8 g of the product of Example 1 in 53 ml of THF at room temperature and the mixture is stirred for 10 minutes at room temperature.

Then 500 ml of Et ₂ O are added and the organic phase is washed successively with an aqueous saturated sodium hydrogen carbonate solution (twice 60 ml) and then with an aqueous saturated sodium thiosulfate solution (twice 60 ml). The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. The oily residue obtained is purified by flash chromatography using a petroleum ether / Et ₂ O mixture (1/1) and then Et ₂ O as the eluent.

you receives 29.31 g (78 mmol) of the desired Connection.

Example 3

you gives a solution of 6.5 g (17.2 mmol) of the amino acid ester of Example 2 in 200 ml of toluene 4.8 g (1.07 equivalents) in succession Triphenylphosphine and 4.65 g (1.46 equivalents) 4-phenylphenol. You stir the reaction medium violently during 5 minutes and then gives 3.70 g (1.07 equivalents) of diisopropyl azodicarboxylate to.

you stirs overnight at room temperature, the reaction medium is filtered off and evaporated to dry up. The oily residue is purified by flash chromatography using an ether / petroleum ether mixture (5/95) as eluent. You get in this way 6.6 g (12.15 mmol) of the desired compound.

Example 4

6.6 g (12.15 mmol) of the amino acid ester of Example 3 are stirred vigorously for 5 hours at room temperature in the presence of 85 ml of formic acid. The reaction medium is then evaporated to dryness and a white solid is obtained, which is taken up in 100 ml of water. The aqueous phase is washed with Et ₂ O (3 times 20 ml) and then made alkaline with sodium bicarbonate. The aqueous basic phase is then extracted with ethyl acetate (3 times 20 ml), the organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo. 1.86 g (6.6 mmol) of the desired compound are obtained.

Example 5

you mixes 1.86 g (6.2 mmol) of the product of Example 4 with 6.5 ml 1 N NaOH and stir overnight at room temperature.

The aqueous phase is washed with ether / ethyl ether (once 10 ml) and concentrated in vacuo. 15 ml of 1N HCl are then added, the white solid obtained is filtered off, washed with water and dried in vacuo over P ₂ O ₅ .

you receives 1.26 g (3.75 mmol) of the hydrochloride of the amino acid (melting point = 225 ° C).

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 6 (Method a)

you feeds a flask with 17.41 g (185.25 mmol) phenol, 14.5 ml THF and 62 ml 9 N NaOH.

you adds 40 g (185.25 mmol) of 1,4-dibromobutane dropwise.

you stirs and heated during 45 minutes to reflux.

After cooling, the mixture is diluted with 50 ml of water and extracted with 100 ml of Et ₂ O. The organic phase is washed with 30 ml of water, dried over MgSO ₄ , filtered and concentrated. The oily residue is distilled in vacuo using a rotary vane pump and the fraction obtained which distils at 80-105 ° C./1 mmHg.

you receives 15.96 g (37%) of a colorless oil.

Example 7 (method b)

An Erlenmeyer flask is successively charged with 11 g (60 mmol) of 4-hydroxydiphenylmethane, 64.8 g (300 mmol) of 1,4-dibromobutane, 41.5 g (300 mmol) of powdered K ₂ CO ₃ and 94 ml of anhydrous DMF ,

The mixture is stirred overnight at room temperature, filtered and the filtrate is taken up in 300 ml of ethyl acetate. The organic phase is washed with an aqueous saturated NaCl solution (3 times 100 ml), dried over MgSO ₄ , filtered and concentrated.

you distills the excess 1,4-dibromobutane in a vacuum and receives 18 g (56.5 mmol) of an oily residue, the one you want Product corresponds.

you prepares the connections of Examples 8 bus 17 according to one of the methods described above (a or b).

Example 18

A solution of sodium is prepared starting from 1.27 g (55.21 mmol) of sodium in 32 ml of EtOH Sodium ethylate to a mixture of 14.3 g (89.37 mmol) of diethyl malonate and 6.78 g (21.27 mmol) of the bromo derivative of Example 7 and heated to reflux for 4 hours.

The mixture is concentrated in vacuo, the residue is taken up in water and extracted with Et ₂ O.

The ether phase is washed 3 times with water, dried over MgSO ₄ , filtered and concentrated. The excess diethyl malonate is removed by distillation in vacuo.

you receives 6.4 g of a yellow oil (Yield 76%).

you prepares the compounds of Examples 19 to 25 according to the same Method as for Example 18 has been described.

Example 26

you gives a solution 6.4 g (16.08 mmol) of the diester of Example 18 in 3 ml EtOH at 0 ° C one solution of 1.09 g (16.51 mmol) of potassium hydroxide in 16 ml of EtOH.

you stirs overnight at 0 ° C.

The medium is then concentrated, the residue is taken up in 100 ml of water and washed with Et ₂ O (2 times 30 ml). The aqueous phase is cooled and acidified with a concentrated hydrochloric acid solution. The aqueous phase is extracted with ether (twice 40 ml), the ether phases are combined, dried over MgSO ₄ , filtered and concentrated. In this way, 4.71 g (79%) of a very viscous yellow oil are obtained.

you prepares the compounds of Examples 27 to 33 by the same Procedure as it is for Example 26 has been described.

Example 34

3.67 g (13.33 mmol) of DPPA and then 1.34 g (13.33 mmol) of NEt _{3 are added} dropwise to a solution of 4.71 g of the monocarboxylic acid of Example 26 in 20 ml of toluene. The mixture is heated at 80 ° C. for 1 hour, brought to room temperature and 1.65 g (15.27 mmol) of benzyl alcohol are added and the mixture is heated at 80 ° C. overnight. The toluene phase is washed successively with water (1 × 10 ml), an aqueous saturated sodium hyd Roe carbonate solution (1 x 10 ml) and with water (1 x 5 ml). The organic phase is dried over MgSO ₄ , filtered and concentrated in vacuo.

you receives in this way 6.5 g of the raw product. It is purified by flash chromatography on silica gel using an ethyl ether / petroleum ether mixture (3/7) as Eluent. You get 4.55 g (9.55 mmol; yield = 75%) of the carbamate (colorless oil).

you prepares the compounds of Examples 35 to 41 by the same Procedure as it is for Example 34 has been described.

Example 42

you solves 1 g (2.04 mmol) of the carbamate of Example 37 in 20 ml EtOH. Then are added 100 ml 10% Pd / C and hydrogenated at a pressure of about 1 bar above Night at room temperature.

The suspension is filtered through Celite and evaporated to dryness. The oily residue is taken up in an aqueous concentrated HCl solution, the aqueous phase is washed with Et ₂ O (2 times 20 ml) and evaporated the aqueous phase to dryness and dries the residue in vacuo over P ₂ O ₅ to constant weight. In this way 0.64 g (yield 80%) of a white solid is obtained. The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 43

you gives a solution 4.55 g (9.55 mmol) of the ester of Example 34 in 20 ml of MeOH 11.5 ml of a 1 N NaOH solution and stir overnight.

you evaporates the MeOH in vacuo and then washes the remaining aqueous phase with ethyl ether (2 times 15 ml).

The basic aqueous phase is cooled to about 5 ° C. and acidified to a pH of 1 with a 1 N HCl solution and extracted with ethyl ether (twice 20 ml). After drying over MgSO ₄ , filtering and concentrating in vacuo, 3.33 g (78%) of a white solid are obtained.

you prepares the compounds of Examples 44 to 50 the same How to do it for Example 43 has been described.

Example 51

you feeds a flask with 0.89 g (1.99 mmol) of the carbamate of the Example 43 and 5 ml of a saturated solution of gaseous HBr in acetic acid. You stir while 2 hours.

The acetic acid is evaporated in vacuo and the oily residue is triturated in anhydrous ethyl ether. It is filtered and washed with ethyl ether. The white solid is dried in vacuo over P ₂ O ₅ and 0.52 g (66%) of the desired amino acid (melting point> 200 ° C.) is obtained.

The ¹ H-NMR spectrum is consistent with the chemical structure.

you prepares the compounds of Examples 52 to 58 the same How to do it for Example 51 has been described.

Example 59

you dilute 9.25 g (23.24 mmol) of the malonic diester Example 18 with 10 ml of water and adds 2.32 g (58.00 mmol) of sodium hydroxide biscuits.

you stirs and heated during 1 hour and 30 minutes to reflux.

It is diluted with water and washed with Et ₂ O (once 15 ml).

The aqueous phase is cooled and acidified to a pH of 1 with a concentrated aqueous hydrochloric acid solution. The mixture is extracted with Et ₂ O (2 × 25 ml), the ether phases are combined, dried over MgSO ₄ , filtered and concentrated. 7.92 g (100%) of a white solid are obtained.

Example 60

you gives a solution of 7.92 g (23.15 mmol) of the malonic dicarboxylic acid of Example 59 in 50 ml AcOEt 1.69 g (23.15 mmol) diethylamine and then 1.04 g (30.40 mmol) of paraformaldehyde.

you receives while 30 minutes to reflux.

The solution is then cooled using an ice / water bath, diluted with 10 ml of water and acidified to a pH of 1 with a 3 N HCl solution. The aqueous phase is separated off, the organic phase is washed with water (1 × 10 ml), dried over MgSO ₄ , filtered and concentrated.

you receives 6.04 g (84%) of a white Solid.

Example 61

you heats a solution 0.44 g (19.13 mmol) sodium in 15 ml anhydrous EtOH. you gives to this solution 1.35 g (19.42 mmol) of hydroxylamine hydrochloride in 1 ml of warm water, cools down 5 ° C from, filtered and washes the precipitate with 2 ml of anhydrous EtOH.

you gives 3 g (9.70 mmol) of acrylic acid Example 60 to the filtrate, stirred and heated for 24 hours to boil at reflux.

It is filtered, washed with water, with EtOH and then with ethyl ether, and 0.71 g of a white solid (22%) is obtained (melting point> 200 ° C.). the ¹ H-NMR spectrum is consistent with the chemical structure.

Example 62

The chlorine derivative of Example 15 is reacted with diethyl malonate according to the procedure described in Example 18. The malonic ester obtained in this way is saponified after Ver procedure of example 59 and receives the desired connection.

Example 63

you decarboxylates the dicarboxylic acid of example 62 by heating embodiment 140 ° C to Stop of gas evolution and maintains the desired Acid.

Example 64

Are added to a suspension of 7.35 g (193.67 mmol) of _LiAlH4 in 210 ml of anhydrous Et ₂ O, a solution of 31.34 g (161.36 mmol) of the acid of Example 63 in 138 ml of anhydrous Et ₂ O Stir overnight at room temperature.

you cools down 5 ° C from time to time gives successively 5.25 ml of water, 5.25 ml of 15% NaOH and 15, 75 ml of water. After stirring while Filter for 2 hours, rinse with ethyl ether and the filtrate is concentrated.

you receives 19.97 g (68%) of the alcohol.

Example 65

A solution of 19.77 g (110.8 mmol) of the alcohol of Example 64 in solution in 135 ml is added to a solution of 48 g (222.67 mmol) of PCC in 220 ml of CH ₂ Cl ₂ cooled to 0 ° C. CH ₂ Cl ₂ . The mixture is stirred for 3 hours at room temperature, filtered through celite, evaporated to dryness and purified by flash chromatography (ethyl ether / heptane, 4/6). 9.94 g (55.77 mmol) of the aldehyde are obtained.

Example 66

you mixed 6.75 g (44.6 mmol) of benzyl carbonate, 6.5 g (44.6 mmol) of diethyl phosphite and 33.5 ml of acetyl chloride to -5 ° C from and gives dropwise 9.94 g (55.77 mmol) of the aldehyde of the example 65 to. You stir while 1 hour at 0 ° C and then over Night at room temperature.

The excess acetyl chloride is removed by evaporation in vacuo and the residue is taken up in 50 ml of CH ₂ Cl ₂ . It is washed successively with water (once 30 ml), with an aqueous saturated sodium bisulfite solution (twice 30 ml), with an aqueous saturated NaHCO ₃ solution (three times 30 ml) and with water (once 60 ml). The organic phase is dried over MgSO ₄ , filtered and concentrated. 20.19 g of the crude product are obtained, which is chromatographed on silica (eluent: Et ₂ O).

you wins 10.93 g (54.5%) of the product in this way.

Example 67

you feeds a flask with 1.3 g (2.4 mmol) of the phosphonate of the Example 66 and 3.5 ml of a 30% solution of gaseous HBr in acetic acid and moves while 24 hours.

It is evaporated to dryness, the oily residue is triturated in anhydrous Et ₂ O, water is added and the solid formed is filtered off. It is dried in vacuo over P ₂ O ₅ and 0.62 g (1.44 mmol) of a white solid is obtained.

Melting point:> 250 ° C

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 68

you solves 4.9 g (21.9 mmol) of triethylphosphonoacetate in 21 ml of anhydrous DMF, cools down 0 ° C and gives Add 0.56 g (21.9 mmol) of NaH in portions. The mixture is stirred at 0 ° C. for 15 minutes.

you gives a solution of 5.33 g (21.9 mmol) of the bromo derivative of Example 16 in 13 ml anhydrous DMF and stir overnight at room temperature.

It is diluted with Et ₂ O, washed with water, the organic phase is dried over MgSO ₄ , filtered and concentrated. 6.9 g of an oily residue are obtained, which is purified by chromatography on silica (eluent: Et ₂ O).

you receives 5.33 g (63%) of an oil.

you receives the compounds of Examples 69 to 71 using the same procedure like that for example 68 described.

Example 72

you stirs one solution of 5.33 g (13.8 mmol) of the derivative of Example 68 in 32 ml of MeOH with 20.7 ml of 1 M LiOH and then heated to boiling for 1 hour Reflux.

The mixture is evaporated to dryness, water is added and the mixture is washed with Et ₂ O. The aqueous phase is acidified with a 1N HCl solution and extracted with Et ₂ O. The ether phases are combined, dried over MgSO ₄ , filtered and concentrated , 3.93 g (79%) of the desired acid are obtained.

you receives the compounds of Examples 73 to 75 using the same procedure such as that described in Example 72.

Example 76

The acid of Example 72 is converted into the procedure described in Example 34 the carbamate 76 µm.

you receives the compounds of Examples 77 to 79 according to the procedure like you for Example 34 has been described.

Example 80

you converts the phosphonate of Example 76 to that in Example 67 described procedure in the aminophosphonic acid derivative um (melting point> 250 ° C).

The ¹ H-NMR spectrum is consistent with the chemical structure.

you receives the compounds of Examples 81 to 83 according to the procedure, like you for Example 67 has been described.

Example 84

you prepares the compound of Example 84 starting from 1,4-dibromobutane and of 4- (cyclohexylmethyl) phenol (Helv. Chem. Acta, Vol. 77 (1994), 1241 and 1255) according to the procedure described for Example 7 (Method b) has been.

Example 85

you prepares the product of Example 85 following the same reaction sequence, the for the synthesis of the compound of Example 51 has been applied.

Melting point: 121 ° C

Example 86

you saponifies the diester of Example 19 using the same procedure like that for Example 59 described.

Example 87

you decarboxylates the dicarboxylic acid of example 86 during 30 minutes at 130 ° C.

A solution of 10.27 g (36.1 mmol) of that obtained after the decarboxylation in 30 ml of anhydrous Et ₂ O is added to a suspension of 1.64 g (1.2 equivalents) of LiAlH ₄ in 47 ml of anhydrous Et ₂ O. Acid. The mixture is stirred overnight at room temperature.

To hydrolysis and filtration give 7.68 g (28.4 mmol) of desired Alcohol.

Example 88

7.65 g (28.4 mmol) of the preceding alcohol in solution in 35 ml of CH ₂ Cl ₂ are added to 12.25 g (2 equivalents) of pyridinium chlorochromate in solution in 56 ml of CH ₂ Cl ₂ at 0 ° C. After 3 hours at room temperature, filter through silica and purify by flash chromatography (eluent: heptane / Et ₂ O, 7/3).

you receives 4.63 g (17.25 mmol) of the aldehyde.

Example 89

523 mg (1.2 equivalents) of NaH are added to a solution of 3.77 g (1.2 equivalents) of trimethyl phosphonoacetate in 52 ml of anhydrous THF at 0 ° C. The mixture is stirred at 0 ° C. for 15 minutes and then a solution of 4.63 g (17.25 mmol) of the aldehyde of Example 88 in 20 ml of anhydrous THF is added and the mixture is stirred rend 4 hours at room temperature.

It is evaporated, water is added, extracted with Et ₂ O, dried over MgSO ₄ and evaporated. It is purified by chromatography on silica (eluent: Et ₂ O / heptane, 1/9).

you receives 2.56 g (7.89 mmol) of the desired Ester.

Example 90

To 2.56 g (7.9 mmol) of the above ester in solution in 26 ml of MeOH are added 16 ml of 1N NaOH. The mixture is heated under reflux for one hour, acidified with 1N HCl, extracted with Et ₂ O, dried over MgSO ₄ , filtered and concentrated.

you receives 2.36 g (7.6 mmol) of the desired Acrylic acid.

Example 91

you treats the above acid following the procedure as described in Example 61.

Melting point: 205 ° C.

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 92

you alkylates the methylmalonic acid diethyl ester with the bromo derivative of Example 7 according to that described in Example 18 Procedure.

Example 93

you treats the product of Example 92 according to the same reaction sequence, like you for the synthesis of the compound of Example 51 has been applied.

Melting point: 196 ° C.

Example 94

you hydrogenates the carbamate of Example 38 using the same procedure, as described in Example 42 and receives the compound of Example 94.

Melting point:> 250 ° C.

Example 95

you applies the same procedure described in Example 66 is, where diethyl phosphite is replaced by diphenyl phosphite.

Example 96

0.5 g (1 mmol) of the compound from the previous example is stirred in 2 ml of HBr / 30% CH ₃ COOH for 2 hours.

It is evaporated to dryness and triturated in dry Et ₂ O until the salt precipitates.

To filtration and drying give 0.4 g of the desired Product.

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 97

0.3 g of NBu ₄ Br and 8 ml of 2N NaOH are added to 1 g (2.22 mmol) of the product from Example 66 and the mixture is stirred at room temperature for 2 days.

The mixture is diluted with water, washed with Et ₂ O and the aqueous phase is acidified with 1 N HCl and then with concentrated H ₂ SO ₄ . The mixture is extracted with Et ₂ O, dried over MgSO ₄ and evaporated to give 0.41 g of the desired product.

Example 98

you cleaves the protective group from the product of Example 97 according to the Procedure described in Example 96.

Example 99

you applies the same procedure described in Example 66 , replacing the aldehyde of Example 65 with tridecanal.

Example 100

you cleaves the protecting group from the product of Example 99 according to the procedure described in Example 67.

Melting point: 252 ° C

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 101

An Erlenmeyer flask is charged successively with 4.4 g (31.67 mmol) of 3-bromo-1-propanol, 4.9 g (26.5 mmol) of 4-hydroxydiphenylmethane, 11 g (79.59 mmol) of powdered K ₂ CO ₃ and 45 ml of anhydrous DMF.

you stirs overnight at room temperature.

It is filtered and the filtrate is taken up in 30 ml of ethyl acetate. The organic phase is washed with water (2 × 10 ml) and then with an aqueous saturated NaCl solution (1 × 10 ml), dried over MgSO ₄ , filtered and concentrated.

you cleans the residue using flash chromatography Silicon dioxide with an ethyl ether / heptane mixture (50/50) and receives 5.35 g (22.07 mmol) of the expected product.

Example 102

you oxidizes the alcohol of Example 101 according to the procedure, which is described in Example 88.

Example 103

2.97 g (1.1 equivalents) of trimethylphosphonoacetate and 0.69 g (1.1 equivalents) of lithium hydroxide are added in succession to a solution of 3.56 g (14.8 mmol) of the aldehyde of Example 102 in 15 ml of anhydrous THF , The mixture is stirred overnight at room temperature under argon. 100 ml of ethyl ether are added and the organic phase is washed with water (2 × 10 ml) and with an aqueous saturated NaCl solution (1 × 10 ml). The organic phase is dried over a molecular sieve, filtered and concentrated. It is purified by chromatography on silica (eluent: Et ₂ O / heptane, 1/9) and 2.27 g (7.66 mmol) of the desired ester are obtained.

Example 104

you saponifies the ester of Example 103 according to the procedure that is described in Example 90.

Example 105

you treats the above acid following the procedure described in Example 61.

Melting point: 240 ° C.

The ¹ H-NMR spectrum is consistent with the chemical structure.

Example 106

A three-necked flask was charged with 10 g (54.28 mmol) of 4-hydroxydiphenylmethane, 1.86 g (0.1 equivalent) of nBu ₄ NBr, 7.2 g (1.5 equivalents) of ethylene carbonate and 100 ml of anhydrous DMF. The mixture is heated at 140 ° C. under argon for 4 hours. The mixture is brought to room temperature, 100 ml of ethyl ether are added and the organic phase is washed with water (3 times 40 ml) and then with an aqueous saturated NaCl solution (1 time 20 ml). The organic phase is dried over a molecular sieve, filtered and concentrated. The residue is purified by flash chromatography on silica with an ethyl ether / heptane mixture (50/50).

you receives 6.4 g of the expected product.

Example 107

2.14 g (1.2 equivalents) of SOCl ₂ and then 76 mg (1.1 mmol) of imidazole are added to 3.41 g (15 mmol) of the alcohol of Example 106 at a temperature of about + 5 ° C. The mixture is stirred at room temperature for 15 minutes and then at 100 ° C. for 4 hours. The mixture is then brought to room temperature and 20 ml of water are added, the aqueous phase is neutralized with NaHCO ₃ and extracted with ethyl ether (twice 20 ml). The organic phase is dried over a molecular sieve, filtered and concentrated. 3.45 g (13.98 mmol) of the expected chlorine derivative are obtained.

Example 108

you prepares the diester of example 108 according to the procedure, which is described in Example 18, but using the chlorine derivative Example 107 is based.

Example 109

you saponifies the diester of Example 108 according to that described in Example 59 Procedure.

Example 110

you decarboxylates the dicarboxylic acid of Example 109 and reduces them according to the procedure that is described in Example 87.

Example 111

you oxidizes the alcohol of Example 110 according to that described in Example 88 Procedure.

Example 112

you converts the aldehyde of Example 111 by a Wittig-Horner reaction according to the Procedure described in Example 103 in the ester of Example 112 µm.

Example 113

you saponifies the ester of Example 112 according to that described in Example 90 Procedure.

Example 114

you treats the acid 113 according to the procedure described in Example 61.

Melting point: 226 ° C.

The ¹ H-NMR spectrum is consistent with the chemical structure.

BIOLOGICAL ACTIVITY

Biological studies of the compounds of the invention

1) Inhibition of the aminopeptidase activity of the recombinant LTA ₄ hydrolase

The compounds were examined using recombinant human LTA ₄ hydrolase (Minami et coll., FEBS Letters, 229 (1988), 279). The LTA ₄ hydrolase expressed by E. Coli JM109 is predominantly purified according to Minami et Coll. (J. Biol. Chem., 262 (1987), 13873).

Inhibition of the aminopeptidase activity of the enzyme is measured using a fluorimetric method with 96-well microtiter plates. The recombinant enzyme (0.5 μg in 50 μl 50 mM Tris-HCl, pH 7.4) is preincubated for 10 minutes at 37 ° C. in the presence of an inhibitor and of dithiothreitol (DTT, 10 ^-5 M). Alanyl-aminomethylcoumarin substrate (25 μM Ala-AMC - 50 mM Tris-HCl, pH 7.4) is added and the incubation is continued at 37 ° C. for 15 minutes. The release of AMC is measured fluorometrically.

to Assessment of specificity of the compounds of the invention some of these compounds were also considered in terms of their ability examines the activity the membrane aminopeptidase M (EC 3.4.11.2) to inhibit. The same Test is made with 0.1 μg Aminopeptidase M (Pierce, USA).

2) in vitro inhibition of LTB ₄ biosynthesis

The biosynthesis of LTB ₄ in whole human blood is measured in the presence of the inhibitors of LTA ₄ hydrolase according to the invention. Pre-incubate a 50 μl blood sample, which was taken over sodium heparinate, at 37 ° C. in the presence of the inhibitor for 10 minutes (50 mM Tris-HCl, 0.15 M NaCl, 10 ^-5 M DTT, pH 7, 4).

The LTA ₄ substrate was previously prepared by alkaline hydrolysis of _LTA4 methyl ester (Cayman Chemical Co., USA). After incubation for 10 minutes in the presence of LTA ₄ (1 μM in 50 mM Tris-HCl, 0.15 M NaCl, 0.5% BSA, pH 7.4), the reaction is interrupted by diluting to 1/20 in the 0.1 M potassium phosphate buffer, 1.5 mM NaN ₂ , 0.4 M NaCl, 1 mM EDTA, 0.1% BSA, pH 7.4, -4 ° C).

The LTB ₄ is determined by enzyme immunoassay (Cayman Chemical Co., USA).

3) ex vivo inhibition of LTB ₄ biosynthesis

The LTA ₄ hydrolase inhibiting compounds of the invention are suspended in 1.25% methyl cellulose and administered orally to mice at a dose of 10 mg / kg. Thirty minutes later you kill the mice and draw the blood over lithium heparin. The blood is then incubated for 10 minutes at 37 ° C in the presence of LTA ₄ , after which the LTB _{4 formed is} determined by enzyme immunoassay.

The compounds of the invention prove in vitro at low concentration (e.g. is the Ki value of the compound of Example 51 32 nM) and oral Low dose administration (<1 mg / kg or <0.1 mg / kg) as active.

The compounds according to the invention, and in particular those which correspond to one of the formulas (II) and (VI), enable the in vitro and in vivo inhibition of LTA ₄ hydrolase. They also enable inhibition of the LTB ₄ biosynthesis, which in fact makes the compounds interesting for human therapy.

The compounds of the invention can in particular to be administered orally.

she have good bioavailability and low toxicity.

The compounds according to the invention, and especially those of the aminophosphonate type have a long one Duration of action.

Thus, these compounds effect complete inhibition of blood LTA ₄ hydrolase activity after oral administration in doses of 1 to 10 mg / kg to the rat for more than 24 hours.

Claims (55)

Compounds of the following formula (I):

in which - X is selected from the following groups: i) -NH ₂

N ₁ and n _{3 represent} 0 or 1, with the proviso that (n ₁ + n ₃ ) is 0 or 1, n _{2 has} a value from 0 to 10, Y is selected from the following groups: i) -O- ii) -CH ₂ - iii) -S- iv) -NH- v) -OCH ₂ - - R ^{1 is} selected from the following groups: i) the hydrogen atom ii) alkyl groups iii) cycloalkyl groups iv) phenyl groups, the are unsubstituted or mono- or polysubstituted with substituents selected from halogen atoms, CF ₃ groups, alkyl groups which contain 1 to 10 carbon atoms and alkoxy groups which contain 1 to 10 carbon atoms, groups of the formulas NH ₂ , NO ₂ , CN, OH , CO ₂ H, OPh, OCH ₂ Ph, SCH ₃ , SCH ₂ CH ₃ and NHCOR ⁶ , v) α- or β-naphthyl groups, vi) anthracene groups, vii) Groups of the formula -A ² - (CH ₂ ) _n4 -A ¹ , in which n _{4 has} a value from 0 to 4, A ¹ and A ^{2 are} independently selected from the following groups: a) cycloalkyl groups b) phenyl groups which are unsubstituted or mono- or polysubstituted by substituents selected from halogen atoms, CF ₃ groups and alkyl groups which contain 1 to 10 carbon atoms and alkoxy groups which contain 1 to 10 carbon atoms, c) 2-, 3- or 4 -Pyridyl d) 2- or 3-thienyl e) 2- or 3-furyl f) 2-, 3- or 4-piperidyl g) cycloalkene viii) 2-, 3- or 4-pyridyl groups ix) 2- or 3- Thienyl groups x) 2- or 3-furyl groups

- Z is selected from the following groups: i) -COOR ⁷

v) -SO ₃ H; vi) -SO ₂ NHR ¹¹ vii) -CONHSO ₂ R ¹¹ - R ² and R ^{3 are} independently selected from the following groups: i) hydrogen atoms ii) alkyl groups containing 1 to 10 carbon atoms iii) alkyl groups containing 1 to 10 Contain carbon atoms and are substituted by a halogen atom iv) CF ₃ groups v) halogen atoms - R ⁴ and R ^{5 are} independently selected from hydrogen atoms, alkyl groups which contain 1 to 10 carbon atoms, phenyl groups which are not substituted or by a halogen atom, a CF ₃ group, an alkyl group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms or an OH group, - n _{5 has} a value of 0 to 2, - R ⁶ an alkyl group means 1 to 10 carbon atoms - R ^{7 represents} a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms represents a group - (CH ₂ ) _n6 -Ph, wherein n _{6 has} a value of 0 to 4 and Ph represents a phenyl group which is unsubstituted or mono- or polysubstituted by a halogen atom, a CF _{3 group} , an alkyl group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms, or an OH group , - R ⁸ and R ^{9 are} independently selected from hydrogen atoms, phenyl groups, alkyl groups containing 1 to 10 carbon atoms and acetylthioalkylene groups containing 1 to 10 carbon atoms, - R ^{10 is} an alkyl group containing 1 to 10 carbon atoms, one group - (CH ₂ ) _n7 -Ph means wherein n _{7 has} a value of 1 to 6 and Ph represents a phenyl group which is unsubstituted or simple or more is substituted by a halogen atom, a CF ₃ group, an alkyl group having 1 to 10 carbon atoms, or an alkoxy group having 1 to 10 carbon atoms, - R ^{11 is} an alkyl group containing 1 to 10 carbon atoms, or a phenyl group means, and their isomers, diastereoisomers and enantiomers and their therapeutically acceptable salts, with the proviso that if: (α) when Z represents a group of the type COOR ⁷ and n ₁ = n ₃ = 0 and R ² = H and R ^{1 represents} an unsubstituted or mono- or polysubstituted phenyl group of type iv), then n ₂ does not have the value 1, and (β) the compound is not α-amino-β-phenoxy-propionic acid, 3-amino-7-phenylheptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α-amino-6-phenyl-hexanoic acid is still α-amino-5-phenoxy-pentanoic acid. Compounds according to claim 1, characterized in that R ² and / or R ^{3 represent} hydrogen atoms. Compounds according to claim 2, characterized in that R ² and R ^{3 represent} hydrogen atoms. Compounds according to claim 1, characterized in that R ² and / or R ³ are different from hydrogen. Compounds according to one of Claims 1 to 4, characterized in that n ₁ and n _{3 have} the value 0. Compounds according to one of claims 1 to 4, characterized in that n ₁ or n _{3 is} different from 0. Compounds according to one of Claims 1 to 6, characterized in that X denotes NH ₂ . Compounds according to one of Claims 1 to 7, characterized in that X denotes NH ₂ and / or Z COOH. Compounds according to one of Claims 1 to 8, characterized in that they correspond to the following formula (II):

in which X, n ₂ , n ₃ , Y, R ¹ and R ^{7 have} the meanings given in claim 1. Compounds according to one of claims 1 to 9, characterized in that they correspond to the following formula (III):

in which Y, n ₂ , n ₃ and R ^{1 have} the meanings given in claim 1. Compounds according to one of claims 1 to 10, characterized in that they correspond to the following formula (IV):

in which Y, n ₂ and n _{3 have} the meanings given above and Ar represents a group R ¹ which denotes an optionally substituted phenyl group iv), as defined in claim 1, or R ^{1 is} a group vii) -A ² - (CH ₂ ) _n4 -A ¹ means in which A ^{2 represents} an optionally substituted phenyl group (b) as defined in claim 1. Compounds according to one of claims 1 to 7, characterized in that X NH ₂ and / or Z

mean in which R ⁸ and R ^{9 represent} hydrogen atoms and R ^{10 has} the meanings given in claim 1. Compounds according to Claim 12, characterized in that X is NH ₂ and Z is -PO (OH) ₂ . Compounds according to one of Claims 1 to 7, 12 or 13, characterized in that they correspond to the following formula (V):

in which X, n ₂ , Y, R ¹ , R ⁸ and R ^{9 have} the meanings given in claim 1. Compounds according to one of Claims 1 to 7 and 12 to 14, characterized in that they correspond to the following formula (VI):

in Y, n ₂ and R ^{1 have} the meanings given in claim 1. Compounds according to one of Claims 1 to 7 and 12 to 15, characterized in that they correspond to the following formula (VII):

in which Y and n _{2 have} the meanings given above and Ar represents R ¹ , which denotes an optionally substituted phenyl group iv), as defined in claim 1, or R ^{1 is} a group vii) -A ² - (CH ₂ ) _{n4 denotes} -A ¹ , in which A ^{2 represents} an optionally substituted phenyl group (b), as defined in claim 1. Compounds according to one of claims 1 to 7, characterized in that they correspond to the following formula (VIII):

in which X, Y, n ₂ , R ¹ , R ⁸ and R ^{10 have} the meanings given in Claim 1. Compounds according to one of Claims 1 to 17, characterized in that n _{2 has} a value from 2 to 5. Compounds according to claim 18, characterized in that n _{2 has} a value of 3. Compounds according to one of claims 1 to 19, characterized in that Y means an oxygen atom. Compounds according to one of claims 1 to 19, characterized in that Y is -CH ₂ -. Compounds according to one of Claims 1 to 21, characterized in that R ^{1 represents} an unsubstituted phenyl group. Compounds according to any one of claims 1 to 10 and 18 to 21 and 31, characterized in that R ^{1 represents} a phenyl group which is mono- or polysubstituted by a group selected from alkyl groups containing 1 to 10 carbon atoms, alkoxy groups which 1 to Contain 10 carbon atoms, groups OPh and OCH ₂ Ph, preferably OPh. Compounds according to one of claims 1 to 21, characterized in that R ¹ _denotes a radical -A ² - (CH ₂ ) _n4 -A ¹ . Compounds according to claim 24, characterized in that A ^{2 represents} a preferably unsubstituted phenyl group. Compounds according to one of Claims 24 and 25, characterized in that n _{4 has} a value of 0 or 1. Compounds according to one of Claims 1 to 13, 21 to 29 and 24 to 26, characterized in that A ^{1 represents} a phenyl group, cycloalkyl group or cycloalkene group. Compounds according to one of claims 24 to 27, characterized in that R ^{1 represents} a phenyl group which is substituted by a group Ph, CH ₂ Ph, CH ₂ cycloalkyl or CH ₂ cycloalkene, preferably CH ₂ Ph or CH ₂ cycloalkyl , Compounds according to one of Claims 24 to 26, characterized in that A ^{1 represents} a phenyl group. Compounds according to any one of claims 24 to 26 and 29, characterized in that R ^{1 represents} a phenyl group which is substituted by a group Ph or CH ₂ Ph, preferably CH ₂ Ph. Compounds according to any one of claims 1 to 21, characterized in that R ^{1 represents} a hydrogen atom or an alkyl group containing 1 to 10 carbon atoms. Compounds according to one of claims 1 to 21, characterized in that R ¹

means in which n _{5 has} the meanings given in claim 1. Compounds according to one of claims 1 to 11 and 18 to 32, characterized in that they are selected out: 1) - (5) -O-4-Benzylphenoxy-serine hydrochloride 2) 2- (RS) -amino-6- (4-benzyl-phenoxy) hexanoic acid hydrobromide 3) 2- (RS) -amino-5- (4-benzylphenoxy) pentanoic acid hydrobromide 4) 2- (RS) -amino-5- (4-phenoxy-phenoxy) pentanoic acid hydrobromide 5) 2- (RS) -amino-7- (4-benzyl-phenoxy) -heptanoic acid hydrobromide 6) 2- (RS) -amino-6- (4-phenyl-phenoxy) hexanoic acid hydrobromide 7) 2- (RS) -amino-6- (4-hexyloxy-phenoxy) -hexanoic acid hydrobromide 8th) 2- (RS) -amino-8- (4-benzyl-phenoxy) octanoic acid hydrobromide 9) 2- (RS) -amino-6- (4-phenoxy-phenoxy) -hexanoic acid hydrobromide 10) 2- (RS) -aminomethyl-6- (4-benzyl-phenoxy) -hexanoic acid 16) 2- (RS) -amino-6- (4-cyclohexylmethyl-phenoxy) -hexanoic acid hydrobromide 17) 3- (RS) -amino-7- (4-benzyl-phenoxy) -heptanoic acid 18) 2- (RS) -amino-2-methyl-6- (4-benzylphenoxy) hexanoic acid hydrobromide 20) 3- (RS) -amino-5- (4-benzyl-phenoxy) -pentanoic acid 21) 3- (RS) -amino-6- (4-benzylphenoxy) hexanoic acid. Compounds according to one of claims 1 to 7 and 12 to 32, characterized in that they are selected out: 11) 1- (RS) -amino-5- (phenoxy) -pentyl-phosphonic acid hydrobromide 12) 1- (RS) -amino-6- (phenoxy) hexyl phosphonic acid hydrobromide 13) 1- (RS) -amino-5- (4-benzyl-phenoxy) -pentyl-phosphonic acid hydrobromide 14) 1- (RS) -amino-4- (phenoxy) butyl phosphonic acid hydrobromide 15) 1- (RS) -amino-7- (phenoxy) -heptyl-phosphonic acid hydrobromide 19) 1- (RS) -amino-tridecanyl phosphonic acid hydrobromide. Compounds according to one of claims 1 to 6, 10, 12, 14 and 17 to 32, characterized in that X

means in which R ⁴ and R ^{5 have} the meanings given in claim 1. Compounds according to one of claims 1 to 7, 17 to 32 and 35, characterized in that R ^{7 is} different from hydrogen. Compounds according to one of claims 1 to 7, 12, 14, 17 to 32 and 35, characterized in that R ⁸ and / or R ^{9 are} independent of one another and different from hydrogen. Compounds according to one of Claims 1 to 7, 17 to 32 and 35, characterized in that R ⁸ and / or R ^{10 are} independent of one another and R ^{8 is} different from hydrogen. Compounds according to any one of claims 35 to 38, characterized in that it selected are made: 22) 2- (RS) -amino-7- (4-benzyl-phenoxy) -heptanoic acid ethyl ester hydrochloride 23) 2- (RS) -amino-6- (4-benzyl-phenoxy) -hexanosäureethylester hydrochloride 24) Diphenyl-1-amino-5-phenoxy-pentyl phosphonate hydrobromide 25) Ethyl-hydrogen-1-amino-5-phenoxy-pentyl phosphonate hydrobromide. Pharmaceutical preparation, characterized in that she as an active ingredient, a therapeutically effective amount of a compound according to one of the claims 1 to 39 in combination with a physiologically acceptable carrier material or binder. Medicament acting as an inhibitor of LTA ₄ hydrolase activity, characterized in that it comprises as active ingredient a compound according to one of Claims 1 to 39. Medicines for anti-inflammatory treatment, characterized in that it as an active ingredient a compound according to any one of claims 1 to 39 includes. Medicines for anti-arthritis treatment, thereby characterized it as an active ingredient a compound according to any one of claims 1 to 39 includes. Medicines for anti-psoriasis treatment, thereby characterized it as an active ingredient a compound according to any one of claims 1 to 39 includes. Medicines for liver protection treatment, thereby characterized it as an active ingredient a compound according to any one of claims 1 to 39 includes. Medicines for antimitotic treatment, thereby characterized it as an active ingredient a compound according to any one of claims 1 to 39 includes. Medicament for the treatment of LTB ₄ overproduction, which is normally triggered by cyclooxyenase inhibitors, characterized in that it comprises as active ingredient a compound according to one of Claims 1 to 39. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for inhibiting LTA ₄ hydrolase activity. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for anti-inflammatory treatment. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for anti-arthritis treatment. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for anti-psoriasis treatment. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for liver protection treatment. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, single or multiple substituted phenyl group of type iv) and n is ₂ = 1, α-amino-β-phenoxy-propionic acid, 3-amino-7-phenyl-heptanoic acid, 3-amino-6-phenoxy-hexanoic acid, α- Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for antimitotic treatment. Use of a compound according to any one of claims 1 to 39 of a compound of formula (I) in which Z represents a group of the type COOR ⁷ , n ₁ = n ₃ = 0, R ² = H, R ^{1 is} an unsubstituted, simple or more Substituted substituted phenyl group of type iv) and n is ₂ = 1, the α-amino-β-phenoxy-propionic acid, the 3-amino-7-phenyl-heptanoic acid, the 3-amino-6-phenoxy-hexanoic acid, the α -Amino-6-phenyl-hexanoic acid or α-amino-5-phenoxy-pentanoic acid for the manufacture of a medicament for the treatment of an LTB ₄ overproduction which has been triggered in particular by a cyclooxygenase inhibitor. Pharmaceutical preparation, characterized in that she as an active ingredient a therapeutically effective amount of a compound according to one of the claims 1 to 52 and a therapeutically effective amount of a cyclooxygenase inhibitor, if any in combination with a physiologically acceptable carrier material or binder.